Cancer promoting transcriptional enhancers controlled by the EMT-activator ZEB1

由 EMT 激活剂 ZEB1 控制的促癌转录增强子

• 批准号: 416775465
• 负责人: Professor Dr. Thomas Brabletz
• 金额: --
• 依托单位: Nikolaus-Fiebiger-Zentrum für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/416775465?language=en
• 关键词: Cancer; promoting; transcriptional; enhancers; controlled

To date, the vast majority of cancer related deaths is caused by the formation of distant metastases. Thus, it is of utmost importance to better understand and predict the metastatic process. During the last two decades we and others could identify cancer cell plasticity, mediated by the embryonic program of Epithelial to Mesenchymal Transition (EMT) and its reverse process (MET), to be a crucial trait driving the metastatic cascade. Our work focuses on the transcription factor ZEB1, a major EMT inducer and known repressor of epithelial genes. We have shown that in aggressive cancers, ZEB1 can turn into a transcriptional activator of tumor-promoting genes. Lately, gene activation via distant transcriptional enhancers emerged as an important metastasis promoting mechanism. Active enhancers are even considered as prognostic and potentially diagnostic tumor markers. Since we have evidence that ZEB1 functions in enhancer activation, we now plan to characterize ZEB1 dependent enhancer regions on a genome wide level. Further, we want to annotate those enhancers to the respective regulated genes and characterize their functions in tumor cell biology. We expect to achieve knowledge about a novel aspect of ZEB1 dependent pro-metastatic functions and to identify novel tumor promoting enhancers that might serve as potential prognostic and diagnostic tools.

到目前为止，绝大多数与癌症相关的死亡是由远处转移的形成造成的。因此，更好地了解和预测转移过程是至关重要的。在过去的二十年里，我们和其他人发现，癌细胞的可塑性是推动肿瘤转移级联反应的关键特征，这种可塑性是由上皮向间充质转化(EMT)及其反向过程(MET)介导的胚胎程序。我们的工作重点是转录因子ZEB1，一个主要的EMT诱导者和已知的上皮基因抑制因子。我们已经证明，在侵袭性癌症中，ZEB1可以转变为肿瘤促进基因的转录激活因子。近年来，通过远距离转录增强子激活基因成为促进肿瘤转移的重要机制。活性增强剂甚至被认为是预后和潜在的诊断肿瘤标记物。由于我们有证据表明ZEB1在增强子激活中发挥作用，我们现在计划在全基因组水平上表征ZEB1依赖的增强子区域。此外，我们希望将这些增强子注释为各自受调控的基因，并表征它们在肿瘤细胞生物学中的功能。我们期望获得有关ZEB1依赖的促转移功能的新方面的知识，并识别可能作为潜在预后和诊断工具的新的促肿瘤增强剂。